REVIEW

The renin–angiotensin system and diabetes: An update

Antônio Ribeiro-Oliveira Jr1 Abstract: In the past few years the classical concept of the renin–angiotensin system (RAS) Anelise Impeliziere has experienced substantial conceptual changes. The identifi cation of the renin/prorenin recep- Nogueira1 tor, the angiotensin-converting enzyme homologue ACE2 as an angiotensin peptide processing Regina Maria Pereira2 enzyme, Mas as a receptor for Ang-(1-7) and the possibility of signaling through ACE, have Walkiria Wingester Vilas contributed to switch our understanding of the RAS from the classical limited-proteolysis linear Boas3 cascade to a cascade with multiple mediators, multiple receptors, and multi-functional enzymes. In this review we will focus on the recent fi ndings related to RAS and, in particular, on its role Robson Augusto Souza dos in diabetes by discussing possible interactions between RAS mediators, endothelium function, Santos4 and insulin signaling transduction pathways as well as the putative role of ACE2-Ang-(1-7)- 5 Ana Cristina Simões e Silva Mas axis in disease pathogenesis. 1Laboratório de Endocrinologia, Keywords: renin–angiotensin system, diabetes, angiotensin II, angiotensin-(1-7), insulin, Departamento de Clínica Médica, endothelium 2Departamento de Ciências Biológicas, Centro Universitário de Belo Horizonte, UNIBH, Belo Horizonte, MG, Brazil; 3Hospital Life Center, Belo Introduction Horizonte, MG, Brazil; 4Laboratório In a classical view, the renin–angiotensin system (RAS) is considered an endocrine de Hipertensão, Departamento de Fisiologia e Biofísica, Instituto de system whose active metabolite, the angiotensin II (Ang II), is produced by enzymatic Ciências Biológicas, UFMG, Belo sequential cleavage from the angiotensinogen substratum of hepatic origin (Weber 5 Horizonte, MG, Brazil; Departamento et al 2001; Zaman et al 2002). In the bloodstream, the renin, a highly specifi c protease, de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais converts the circulating angiotensinogen into the decapeptide Ang I, which, in turn is (UFMG), Belo Horizonte, MG, Brazil converted to Ang II by the angiotensin-converting enzyme (ACE) action (Weber et al 2001; Zaman et al 2002). This enzyme also inactivates bradykinin (BK) and is highly found in the endothelial cells membranes of the pulmonary circulation (Weber et al 2001; Zaman et al 2002; Carey and Siragy 2003a). In the past few years the classical concept of the RAS has experienced substantial conceptual changes. Although this system is known for decades, recent discoveries in cellular and molecular biology, as well as cardiovascular and renal physiology, have introduced larger understanding about its function in physiological situations and in several diseases (Carey and Siragy 2003a; Chappell et al 2004; Simões e Silva et al 2006a; Santos and Ferreira 2007; Chappell 2007). One of the most relevant conceptual changes in our understanding of the RAS was the discovery of local or tissue RAS (Miyazaki and Takai 2006; Paul et al 2006). A local system is characterized by the presence of RAS components, such as angioten- Correspondence: Ana Cristina Simões sinogen, processing enzymes, angiotensins, and specifi c receptors at tissue level. In Silva Avenida Bernardo Monteiro, 1300 the 70’s, Ganten and colleagues (1971) demonstrated, for the fi rst time, that all RAS’s apto 1104, Bairro Funcionários, components could be produced locally in several organs and tissues. The local RAS Belo Horizonte, Minas Gerais, Brazil, 30150-281 has been found in the heart, blood vessels, kidney, adrenal gland, pancreas, central Tel +55 31 7814 8682 nervous system, reproductive system, lymphatic and adipose tissue (Nielsen et al 2000; + Fax 55 31 3227 5555 Sernia 2001; Lavoie and Sigmund 2003; Spät and Hunyady 2004). The local systems Email [email protected], [email protected] appear to be regulated independently of the circulatory RAS but can also interact with

Vascular Health and Risk Management 2008:4(4) 787–803 787 © 2008 Ribeiro Oliveira et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Ribeiro-Oliveira et al

the latter. In this way, local RAS’s effects could occur in II-AT1 receptor-mediated actions, especially vasoconstriction the cell that produces the peptides (intracrine and autocrine and proliferation (Simões e Silva et al 2006a; Santos and functions), in adjacent cells (paracrine function) or through Ferreira 2007; Chappell 2007). Furthermore, Ang-(1-7) has the bloodstream to a specifi c organ or tissue (endocrine been associated to the physiopathology of several diseases function) (Miyazaki and Takai 2006; Paul et al 2006). The such as hypertension (Luque et al 1996; Ferrario et al 1998; main importance of tissue RAS is linked to local regulatory Simões e Silva et al 2004, 2006b, 2006c), pre-eclampsia mechanisms that contribute to a great number of homeostatic (Merril et al 2002; Brosnihan et al 2004; Shah 2005), hyper- pathways, including cellular growth, extracellular matrix trophic myocardial disease and congestive heart failure, formation, vascular proliferation, endothelium function and myocardial infarct (Zisman et al 2003; Santos and Ferreira apoptosis (Miyazaki and Takai 2006; Paul et al 2006). 2005), chronic renal diseases (Simões e Silva et al 2006b), Other important landmarks for the new concept of RAS hepatic cirrhosis (Paizis et al 2005; Pereira et al 2007; Herath were the characterization of angiotensin-(1-7) [Ang-(1-7)] as et al 2007; Warner et al 2007), diabetic nephropathy (Carey a biological active metabolite of RAS (Simões e Silva et al and Siragy 2003b; Tikelis et al 2003; Kalantrina and Okusa 2006a; Santos and Ferreira 2007), the Ang IV receptor as 2006), and gestational diabetes (Nogueira et al 2007). an insulin-regulated aminopeptidase (IRAP) (Albiston et al This review will summarize the current aspects of RAS, 2001), the renin/prorenin receptor (Nguyen et al 2002), the its role in diabetes, and its well-known and putative inter- ACE homologue ACE2 as an angiotensin peptide processing actions with endothelium function and insulin signaling. enzyme (Donoghue et al 2000; Tipnis et al 2000), Mas as a Moreover, the importance of the RAS to diabetes prevention receptor for Ang-(1-7) (Santos et al 2003), and the possibil- and its involvement on cardiovascular and renal events in ity of signaling through ACE (Kohlstedt et al 2004). These diabetic patients will be discussed. discoveries have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade New aspects of the RAS to a cascade with multiple mediators, multiple receptors, and components multi-functional enzymes (Simões e Silva et al 2006a; Santos Angiotensinogen and Ferreira 2007; Chappell 2007) (Figure 1). Angiotensinogen (AGT) is a glycoprotein of 452 aminoacids In regard to Ang-(1-7), the identifi cation of ACE2 and produced in the liver as well as in other tissues (including the Mas as a receptor implicated in its actions contributed to heart, vessels, kidneys, and adipose tissue), which circulates decisively establish this heptapeptide as a biologically active as an inactive biological peptide. Through renin action, it is member of the RAS cascade. Most evidence supports a converted into Ang I, the precursor peptide in classical RAS counter-regulatory role for Ang-(1-7) by opposing many Ang cascade (Weber et al 2001). The M235T polymorphism of the AGT gene is known Angiotensinogen Ang (1-9) to be associated with circulating and tissue AGT (Bloem ACE 2 Renin et al 1995; Winkelmann et al 1999; Gumprecht et al 2000). Endopeptidases Receptor Ang I Ang (1-7) However, the fi nding of genetic linkage between the AGT ACE ACE 2 gene and hypertension in many studies and the presence Ang II Ang IV Ang II Ang of increased levels of plasma AGT in subjects with higher Fragments IRAP parental and personal blood pressure only support a role for Receptor Receptor Bradykinin

Receptor AT2 increased synthesis of angiotensinogen in hypertension but do Vasoconstriction Vasodilation Bradykinin AT 4 fragments not explain how this translates into elevated blood pressure Na retention Natriuresis (Naber and Siffert 2004). One hypothesis is that the genetic Aldosterone and Apoptosis Mas AVP release NO, Vasodilation increase in RAS activity due to the T235 allele of AGT may Dipsogenic action prostaglandins Anti-proliferation lead to greater formation of Ang II in cardiac, vascular, and Proliferation Anti-thrombosis renal tissues, predisposing to cardiovascular and renal dam- Thrombotic Anti-fibrosis age (Winkelmann et al 1999; Gumprecht et al 2000). Fibrogenic Anti’fibrosis

Figure 1 Novel components of the renin–angiotensin system and its interactions. Renin Abbreviations: Ang, angiotensin, AT , AT , angiotensinergic receptors types 1 and 2; 1 2 Renin is an aspartyl protease enzyme produced by the jux- NO, nitric oxide; ACE, angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2. taglomerular apparatus of the kidney. This enzyme acts on

788 Vascular Health and Risk Management 2008:4(4) RAS and diabetes

AGT and forms the decapeptide Ang I. Renin is considered For example, in contrast to classical ACE, ACE2 does not a key enzyme of the RAS due to the rate-limiting nature of metabolize BK. its hydrolytic activity on the precursor AGT (Weber et al In the original work of Donoghue and colleagues (2000), 2001; Zaman et al 2002). ACE2 was described as having as a primary activity the In recent years, this view has acquired new and important hydrolysis of Ang I, generating Ang-(1-9), serving as an indi- features after the discovery of the renin/prorenin receptor rect pathway to generate Ang II. However, this interpretation by Nguyen and colleagues (2002). Thus, according to our was challenged by the demonstration that Ang II was the pref- new understanding of the role of renin within the RAS, it erable substrate for ACE2 (Tipnis et al 2000; Vickers et al serves as an Ang II-generating enzyme through the limited- 2002). Indeed, the catalytic effi ciency of ACE2 against Ang proteolysis process started by its action on AGT and it can II is 400-fold higher than for Ang I and leads to Ang-(1-7) act as an agonist of the RAS inducing signaling through its formation (Rice et al 2004). It is also functionally remarkable receptor. In addition, binding of renin to its receptor appears that ACE2 is the main enzyme for Ang-(1-7) generation in to increase its catalytic effi ciency on its substrate. We are many tissues (Rice et al 2004; Ferrario et al 2005). still searching for the biological and physiopathological Taking into account the enzymatic properties of the implications of these actions, but there are suggestions that two ACEs and of the two main RAS mediators, Ang it may be implicated in target-organ lesion, especially in the II and Ang-(1-7), we can make out a new vision of the kidney (Staessen et al 2006). RAS. In this novel concept, the RAS can be seen as a dual function system in which the vasoconstrictor/proliferative Angiotensin-converting enzyme or vasodilator/antiproliferative actions are primarily driven The key role of angiotensin-converting enzyme (ACE) within by the ACE/ACE2 balance (Simões e Silva et al 2006a; the RAS is well established since the pioneering work of Santos and Ferreira 2007; Chappell 2007; Warner et al Skeggs and colleagues (1956), which showed that ACE is 2007). According to this concept, an elevated ACE activity the main Ang II-generating enzyme. About 40 years later, concomitant with a reduced ACE2 activity will lead to the action of ACE in the catabolism of Ang-(1-7) was clearly increased Ang II generation and increased catabolism of established (Deddish et al 1998). As shown in Figure 1, by Ang-(1-7)-favoring vasoconstriction, while the opposite forming the potent vasoconstrictor Ang II and inactivating the profi le (elevated ACE2 activity with reduced ACE activity) vasodilator Ang-(1-7), ACE plays a central role as a pressor will decrease Ang II levels by converting it into Ang-(1-7), enzyme. Another action outside the RAS, the inactivation of which, in turn, promotes vasodilation (Simões e Silva et al the vasodilator BK, further strengthens the role of ACE as a 2006a; Santos and Ferreira 2007; Chappell 2007; Warner pro-hypertensive enzyme. et al 2007). However, the role of ACE is not restricted to its hydro- lytic activity. Fleming and colleagues (Kohlstedt et al 2004) Angiotensin II have identifi ed a new action of ACE: the out-in signaling. Ang II was isolated in 1940 by Braun-Menendez and col- According to this novel view, upon binding by bradykinin leagues (1940) and Page and Helmer (1940) and was fi rstly (BK) and ACE inhibitors (ACEi), ACE is phosphorylated at characterized as a potent vasoconstrictor that increases the amino acid Ser1270 and triggers a signal cascade, which peripheral vascular resistance and consequently elevates was able to increase ACE and COX-2 synthesis. In addition, arterial pressure. In situations of extracellular fl uid volume the signaling through ACE was described in adipocytes and contraction, Ang II reduces renal sodium excretion via altera- pre-adipocytes (Kohlstedt et al 2004). tions in renal hemodynamics, direct enhancement of proximal tubule sodium bicarbonate reabsorption, and aldosterone- Angiotensin-converting enzyme 2 mediated increases in late distal tubule and cortical collecting In 2000, two independent groups (Donoghue et al 2000; duct reabsorption (Hall 1991; Ichikawa and Harris 1991; Tipnis et al 2000) identifi ed a new enzyme homologue of Hall et al 1999; Brewster and Perazella 2004). Ang II also ACE, which they called angiotensin-converting enzyme 2 increases thirst, salt appetite, and intestinal sodium absorp- (ACE2) (Donoghue et al 2000) and captopril insensitive tion, all of which increase the extracellular fl uid volume. In carboxypeptidase (Tipnis et al 2000). This enzyme shows a this context, the RAS was initially defi ned as an endocrine homology of about 42% with ACE, but different biochemi- system in which circulating Ang II regulates blood pressure cal activities, being highly specifi c for angiotensin cleavage. and electrolyte balance via its actions on vascular tone,

Vascular Health and Risk Management 2008:4(4) 789 Ribeiro-Oliveira et al

aldosterone secretion, renal sodium handling, thirst, water and Schiffrin 2000). In humans, AT1 receptor is widely intake, sympathetic activity, and vasopressin release. expressed in blood vessels, heart, kidney, adrenal glands, and

Additional experimental studies as well as clinical tri- liver, whereas AT2 receptor is present mainly in fetal tissue, als using ACE inhibitors and Ang II type 1 (AT1) recep- decreasing rapidly after birth, with relatively low amounts tor blockers have shown that the actions of this system normally expressed in adult tissue. The G protein-coupled extend far beyond blood pressure control and electrolyte AT1 receptor mediates the known physiological and patho- balance (Ferrario et al 2004). It has become clear that the logical actions of Ang II and undergoes rapid desensitization deleterious actions of RAS on cardiovascular remodeling and internalization after agonist stimulation. In contrast, the and renal function account for the benefi cial effects of the AT2 receptor does not exhibit the latter features and acts

ACE inhibitors and AT1 receptor blockers in patients with mainly through Gi and tyrosine phosphatases to exert pre- hypertension, left ventricular hypertrophy, heart failure, dominantly inhibitory actions on cellular responses mediated and diabetic nephropathy (Ferrario et al 2004). However, by the AT1 receptor and growth factor receptors (Nouet and besides circulating RAS, Ang II as well as other RAS Nahmias 2000; Hunyady and Catt 2006). For example, both mediators can also be locally produced and exert paracrine, receptors play a role in regulating vascular smooth muscle intracrine, and autocrine effects (Myiazaki and Takai 2006). cell (VSMC) function, although they differ in their actions.

One of the fi rst evidence for the tissue formation of Ang II While the AT1 receptor is associated with growth, infl am- came from studies on angiotensin metabolism in sheep (Fei mation and vasoconstriction, the AT2 receptor is generally et al 1980). The octapeptide was subsequently found to be associated with opposite actions stimulating apoptosis and produced in numerous tissues, including the adrenal, brain, vasodilatation (Touyz and Schiffrin 2000). heart, kidney, vasculature, adipose tissue, gonads, pancreas, Animal models and clinical data have also helped to prostate, eye, and placenta (Nielsen et al 2000; Sernia 2001; establish that inhibition of Ang II action in nonclassical Lavoie and Sigmund 2003; Spät and Hunyady 2004; Navar target sites, such as immune cells, explains some of the and Nishiyama 2004; Brewster and Perazella 2004). Further unanticipated therapeutic effects of ACE inhibitors and AT1 investigations proposed that in the circulating RAS, renin receptor blockers (Ferrario et al 2004). Parallel studies on the originating from the kidney is a rate-limiting factor for Ang molecular mechanism of action of Ang II have revealed that

II generation in plasma, but in the vascular tissue, ACE and its main target, the AT1 receptor, is one of the most versatile other peptidases such as chymase regulate Ang II generation members of the G protein-coupled receptor (GPCR) family (Myiazaki and Takai 2006). Although not all components of (Hunyady and Catt 2006). Ang II exerts several cytokine- the classical RAS are synthesized locally in some tissues, like actions via the AT1 receptor and can stimulate multiple alternative enzymatic pathways or the presence of the renin signaling pathways, activate several growth factor recep- receptor, which binds to and activates circulating renin and tors, and promote the formation of reactive oxygen species prorenin (Nguyen et al 2002), may also permit local Ang II (ROS) and other proinfl ammatory responses (Hunyady and formation. In addition, the RAS is also able to exert intracrine Catt 2006). effects due to the intracellular formation of Ang II (Re 2003; Baker et al 2004). However, kinetic studies suggest that Angiotensin-(1-7) intracellular Ang II is largely derived from receptor-mediated Ang-(1-7) was regarded as an inactive component of the uptake of the extracellular peptide (Danser 2003). RAS for many years. However after the demonstration that The cellular Ang II receptor was identifi ed in 1974 as a Ang-(1-7) was the main product formed from Ang I through high-affi nity plasma membrane-binding site that is sensitive an ACE-independent pathway, in dog brain micro-punches to guanyl nucleotides (Glossmann et al 1974). Later, distinct homogenates (Santos et al 1988) and the demonstration that

AT1 and AT2 receptor subtypes were identifi ed by selective this heptapeptide was equipotent to Ang II to elicit vasopres- ligands (De Gasparo et al 2000) and were subsequently sin release from neurohyphophyseal explants (Schiavone et al characterized as seven transmembrane receptors by molecular 1988) and to decrease blood pressure upon microinjection cloning (Murphy et al 1991; Sasaki et al 1991; Kambayashi into the nTS (Campagnole-Santos et al 1989), the importance et al 1993; Mukoyama et al 1993). Thus, Ang II mediates of Ang-(1-7) within the RAS became increasingly evident. effects via complex intracellular signaling pathways that Ang-(1-7) is formed from Ang II by prolylendopep- are stimulated following binding of the peptide to its cell- tidase, prolyl-carboxipeptidase or ACE2 or directly from surface receptors, AT1 and AT2 (Murphy et al 1991; Touyz Ang I through hydrolysis by prolylendopeptidase and

790 Vascular Health and Risk Management 2008:4(4) RAS and diabetes endopeptidase 24.11 and it is metabolized by ACE to Ang- well as augments aldosterone release (Plovsing et al 2003). (1-5) (Donoughue et al 2000; Tipnis et al 2000; Chappell et al Ang III does not affect renal function in humans (Plovsing

2004; Rice et al 2004). ACE inhibitors elevate plasma Ang- et al 2003), but it induces natriuresis probably through AT2

(1-7) concentrations by both increasing Ang I, the substrate receptors stimulation in AT1 receptor-blocked rats (Padia for Ang-(1-7), as well as by preventing Ang-(1-7) degrada- et al 2006). In addition, in cultured renal cells this peptide tion (see Figure 1). Ang-(1-7) is present in the circulation stimulates the expression of many growth factors, proinfl am- and in many tissues including heart, blood vessels, kidney matory mediators, and extracellular matrix proteins (Ruiz- and liver (Simões e Silva et al 2006a; Santos and Ferreira Ortega et al 2000). Ang III normally binds to AT1 and with

2007; Chappell 2007). more affi nity to AT2 receptors (Padia et al 2007). However, The recent identifi cation of ACE2 which forms Ang-(1-7) it is still not established whether these effects of Ang III are from Ang II (Donoughue et al 2000; Tipnis et al 2000), due to direct action of this peptide at angiotensins` recep- and the G-protein coupled receptor Mas as an Ang-(1-7) tors or they are mediated by smaller peptides formed as a receptor (Santos et al 2003) have provided biochemical and consequence of its degradation. molecular evidence for the biological signifi cance of the Ang-(1-7). In addition, the inhibitory effects of Ang-(1-7) on Angiotensin IV Ang II-induced vasoconstriction, and its growth-inhibitory, Ang IV was generated by the enzyme aminopeptidase N, antiarrhythmogenic and antithrombogenic effects imply a which removes the amino acid arginine from the N-termi- counter regulatory role for this angiotensin within the RAS nus of Ang III sequence. Alternatively, this angiotensin and suggest that this may be a potential target for develop- fragment can be also formed directly from Ang II by the ment of new drugs (Simões e Silva et al 2006a; Santos and enzyme D-aminopeptidase. Central administration of Ang IV Ferreira 2007; Chappell 2007). markedly enhances learning and memory in normal rodents In this regard, recent studies suggest that, at least in part, and reverses memory defi cits observed in animal models the benefi cial effects of ACE inhibitors in heart and kidney of amnesia (Chay et al 2004; Braszko et al 2006). In the diseases may be attributed to Ang-(1-7) (Simões e Silva kidney, Ang IV increases renal cortical blood fl ow without et al 2006a; Santos and Ferreira 2007). These fi ndings are altering systemic blood pressure and decreases Na+ transport in agreement with the hypothesis that the RAS is capable to in isolated renal proximal tubules (Chay et al 2004). On the self-regulate its activity through the formation of Ang-(1-7). other hand, other studies have shown that this peptide can In addition, Kostenis and colleagues (2005) recently demon- decrease total and regional renal blood fl ow in rats (Li et al strated that the Ang-(1-7) G-protein coupled receptor Mas 2006). It has been reported that Ang IV induces vasodilation can hetero-oligomerize with AT1 receptor and by so inhibit in preconstricted endothelium-intact but not endothelium- the actions of Ang II. Indeed, Mas receptor acts in vivo as denuded pulmonary artery through a specifi c binding site an antagonist of the AT1 receptor (Kostenis et al 2005). We that is blocked by divalinal (Chen et al 2000). In addition, currently believe that RAS can act through two opposite this peptide increases endothelial NO synthase activity and arms: the major one responsible for the main actions of cellular cGMP content in porcine pulmonary arterial endothe- this system is constituted by the ACE-Ang II-AT1 receptor lial cells (Patel et al 1998). In the heart, Ang IV reduced left axis and the other, a counterregulatory arm, is formed by ventricular pressure-development and ejection capabilities the ACE2-Ang-(1-7)-Mas axis (Simões e Silva et al 2006a; but increased the sensitivity of pressure development during Santos and Ferreira 2007). the systole and speeded relaxation (Slinker et al 1999). Most Ang IV actions are mediated by a specifi c binding

Angiotensin III site called AT4 receptor. This receptor is found in many Ang III is generated from the metabolism of Ang II by ami- organs such as brain, adrenal gland, kidney, lung, and heart nopeptidase A, which cleaves the Asp1-Arg2 bound. Ang III and it mediates the majority of Ang IV actions (Chay et al is a biologically active peptide of the RAS whose effects are 2004; Albiston et al 2007). However, in some circumstances, essentially similar to those observed for Ang II though less Ang IV can induce its effects by interacting with AT1 recep- potent. Ang III enhances blood pressure, vasopressin release, tor (Li et al 2006). It is important to mention that Ang IV and thirst when it is centrally administrated (Cesari et al is not the only ligand for AT4 receptor, since other peptides 2002). Ang III infusion increases blood pressure in healthy such as LVV-hemorphin 7 can bind to this receptor (Albsi- volunteers and hypertensive patients (Suzuki et al 1984) as ton et al 2004). The AT4 receptor has been also identifi ed

Vascular Health and Risk Management 2008:4(4) 791 Ribeiro-Oliveira et al as the transmembrane enzyme, insulin-regulated membrane as higher in end-stage renal disease patients. In a different way aminopeptidase (IRAP) (Albiston et al 2001). IRAP is a from other angiotensin fragments, Des[Asp1]-[Ala1]-Ang II type II integral membrane spanning protein belonging to is generated by decarboxylation reaction instead of cleavage the M1 family of aminopeptidases and is predominantly process. Thus, the fi rst amino acid of the Ang II sequence found in GLUT4 vesicles in insulin-responsive cells. Three (aspartic acid) is converted into alanine. Conventional enzyme hypotheses for the memory-potentiating effects of the AT4 immunoassays do not distinguish between Ang II and Ang A. receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are Otherwise, these assays quantify the sum of Ang II and Ang proposed: acting as potent inhibitors of IRAP, they may A. Ang A has similar affi nity to the AT1 receptor as Ang II, prolong the action of endogenous promnestic peptides; they but a higher affi nity to the AT2 receptor. However, its activity may modulate glucose uptake by modulating traffi cking of in in vitro preparations is lower when compared with Ang II. GLUT4; IRAP may act as a receptor, transducing the signal Indeed, Ang A is a less potent and only partial agonist at the initiated by ligand binding to its C-terminal domain to the AT1 receptor. On the other hand, due to its high affi nity to the intracellular domain that interacts with several cytoplasmic AT2 receptor, it could be an endogenous Ang II regulatory proteins (Chay et al 2004; Albiston et al 2007). However, the peptide (Jankowski et al 2007). precise meaning of this fi nding remains to be elucidated. The demonstration of endogenous Ang-(1-12) in the rat may foretell renin-independent pathways that lead to the Other angiotensin peptides formation of biologically active peptides (Nagata et al 2006). The physiological relevance of other angiotensin peptides Indeed, the peptide bond Tyr12-Tyr13 hydrolyzed to produce is still unclear. Indeed, many studies have been showing the Ang-(1-12) from rat angiotensinogen is structurally distinct presence of these angiotensins in diverse clinical conditions. from the Leu10-Leu11 bond recognized by rat renin to form It is possible that the formation of other angiotensins could be Ang I. Moreover, these bonds are also distinct for human an alternative mechanism to override different levels of RAS angiotensinogen (Nagata et al 2006). Despite the absence of blockade, thus interfering with the action of ACE inhibitors a functional effect attributed to Ang-(1-12), the processing or AT1 receptor blockers. to this intermediate peptide may comprise another level of Recent reports have attributed some biological actions to RAS regulation. the smaller fragment of the RAS as the Ang-(3-7). A result of Tables 1 and 2 summarize the results obtained by recent the degradation of Ang-(1-7), Ang II, and Ang IV by amino- basic and clinical research on RAS. peptidase or carboxypeptidase, it is believed that this angio- tensin plays important role in the brain (Karwowska-Poleska RAS and diabetes et al 1997) and kidney (Handa 1999). Indeed, Ang-(3-7) has The association of the RAS with the endocrine system is par- an affi nity for AT4 receptors that did differ from Ang IV. ticularly illustrated by the prominent role of Ang II in diabetes The issue whether Ang-(1-9) itself has direct biological and metabolic syndrome. The frequent association of diabetes effects or whether its supposed actions are elicited by genera- mellitus (DM) with hypertension, retinopathy, nephropathy, tion of different metabolites, especially Ang-(1-7), remains and cardiovascular disease has implicated the RAS in the initia- unsolved. In some pathological conditions, its concentration tion and progression of these disorders. This has been demon- changes signifi cantly, indicating that it could be involved strated by clinical trials in which RAS inhibitors signifi cantly in those diseases (Ocaranza et al 2006). Ang-(1-9) can be reduced the incidence of vascular complications in DM patients formed direct from Ang I through catalytic action of ACE2 (UKPDS 1998; HOPE 2000; Brenner et al 2001; Lewis et al and it is metabolized by ACE and NEP to generate Ang- 2001; Parving et al 2001; Jandeleit-Dahm et al 2005). These (1-7) (Rice et al 2004). It has been reported that this peptide improvements appear to result from protective actions upon enhances BK actions, increases NO and arachidonic acid skeletal muscle (Muller et al 1997; Frossard et al 2000) and pan- release (Jackman et al 2002), and is involved in the regulation creatic islets (Lupi et al 2006), and also from enhanced insulin of platelet function (Mogielnicki et al 2003). sensitivity associated with decreased adipocyte size (Furuhashi Ang A, also a novel angiotensin peptide, was fi rstly et al 2004), as well as increased transcapillary glucose transport detected in plasma from healthy humans and in end-stage (Muller et al 1997; Frossard et al 2000). Ang II can also cause renal disease patients (Jankowski et al 2007). Ang A concen- insulin resistance by interfering with the insulin-stimulated trations were less than 20% of the Ang II concentrations in increase in insulin receptor substrate 1-associated PI3K activity healthy subjects, but the ratio of Ang A/Ang II has been shown (Folli et al 1999) (Figure 2).

792 Vascular Health and Risk Management 2008:4(4) RAS and diabetes

Table 1 Summary of recent basic research on renin–angiotensin system

Author Results/Interpretations

Abdalla et al 2000 AT1 receptor and the bradykinin (B2) receptor also communicate directly with each other. Albiston et al 2001 The AT(4) receptor is insulin-regulated aminopeptidase and possibly the AT(4) receptor ligands may exert their effects by inhibiting the catalytic activity of insulin-regulated aminopeptidase. Baker et al 2004 Losartan did not block the growth effects of Ang II, excluding the involvement of extracellular Ang II and the plasma membrane AT1 receptor. These data demonstrate a previously unknown growth mechanism of Ang II in the heart. Benter et al 2008 Ang-(1-7) decreased the elevated levels of renal NADPH oxidase (NOX) activity and attenuated the activation of NOX-4 gene expression in the diabetic SHR kidney. Clark et al 2008 c-Jun N-terminal kinase mediates Ang II-specifi c astrocyte proliferation. Donoghue et al 2000 This study identifi es ACE2 as the fi rst known human homologue of ACE, an enzyme that plays a central role in vascular, renal, and myocardial physiology. In contrast to ACE, however, ACE2 is highly tissue-specifi c: whereas ACE is expressed ubiquitously in the vasculature, human ACE2 is restricted to heart, kidney, and testis. Ferrario et al 2004 Lisinopril augmented plasma levels and urinary excretion rates of Ang I and Ang-(1-7), while plasma Ang II was reduced with no effect on urinary Ang II. Losartan produced similar changes in plasma and urinary Ang-(1-7) but increased plasma Ang II without changing urinary Ang II excretion. This study revealed a role for ACE2 in Ang-(1-7) formation from Ang II in the kidney of normotensive rats as primarily refl ected by the increased ACE2 activity measured in renal membranes from the kidney of rats given either lisinopril or losartan. Fraga-Silva et al 2008 This study is the fi rst to show the presence of Mas protein and specifi c binding for Ang-(1-7) in rat and mouse plate- lets. It also suggests that the Ang-(1-7) antithrombotic effect involves Mas-mediated NO release from platelets. Furuhashi et al 2004 RAS blockade decreases adipocyte size in rats without change in epididymal %fat pads accompanied by improvement in insulin sensitivity. Gallagher et al 2004 The results of this study suggest that Ang-(1-7) inhibits lung cancer cell growth through the activation of an angiotensin peptide receptor and may represent a novel chemotherapeutic and chemopreventive treatment for lung cancer. Herath et al 2007 RAS activation in chronic liver injury was shown to be associated with upregulation of ACE2, Mas and hepatic conversion of angiotensin II to angiotensin-(1-7) leading to increased circulatting angiotensin-(1-7). Jackman et al 2002 The two derivatives of Ang I, Ang 1-9, and Ang 1-7, liberated by enzymes in heart tissues, were shown to enhance the local effects of kinins by augmenting NO and arachidonic acid release. Jankowski et al 2007 Ang A was shown to be a novel human strong vasoconstrictive angiotensin-derived peptide. Plasma Ang A concentration seems to be increased in end-stage renal failure. Because of its stronger agonism at the AT2 receptor, it is suggested that Ang A may modulate the harmful effects of Ang II. Kohlstedt et al 2004 ACE was shown to be involved in outside-in signaling in endothelial cells and “ACE signaling” was suggested to be an important cellular mechanism contributing to the benefi cial effects of ACE inhibitors Kostenis et al 2005 This study showed that Mas can hetero-oligomerize with the AT1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor. Lau et al 2004 The data coming from this study indicate the existence of an islet angiotensin-generating system of potential importance in the physiological regulation of glucose-induced insulin secretion, thus diabetes mellitus. Lupi et al 2006 RAS molecules were shown in human islets and their expression was sensitive to glucose concentration. ACE inhibitors, and in particular zofenoprilat, protected human islets from glucotoxicity and the effects of ACE inhibition were associated with decreased oxidative stress. Maia et al 2004 This study suggests that endogenous Ang-(1-7) and/ or an Ang-(1-7)-related peptide plays an important role in the BK potentiation by ACEI through a mechanism not dependent upon inhibition of ACE hydrolytic activity. Nagata et al 2006 The identifi cation of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin. Nguyen et al 2002 This study highlights the role of the cell surface in angiotensin II generation and opens new perspectives on the tissue renin-angiotensin system and on renin effects independent of angiotensin II. Paizis et al 2005 ACE2 expression is signifi cantly increased in liver injury in both humans and rat, and may modulate RAS activity in cirrhosis. Pereira et al 2007 This study showed in a model of hepatic fi brosis the RAS activation. It also suggested that Ang-(1-7) played a protective role in hepatic fi brosis.

(Continued)

Vascular Health and Risk Management 2008:4(4) 793 Ribeiro-Oliveira et al

Table 1 Continued Sampaio et al 2007a This study demonstrated that, in human endothelial cells, Ang-(1-7) negatively modulates Ang II/Ang II type 1 receptor-activated c-Src and its downstream targets ERK1/2 and NAD(P)H oxidase. They also show that SHP-2-c-Src interaction is enhanced by Ang-(1-7). Sampaio et al 2007b They demonstrated that Ang-(1-7), through Mas, stimulates eNOS activation and NO production via Akt- dependent pathways. Santos et al 2008 The results from this study showed that Mas defi ciency in FVB/N mice leads to dramatic changes in glucose and lipid metabolisms, inducing a metabolic syndrome-like state. Sarzani et al 2008 Cell proliferation was progressively stimulated by increasing Ang II concentrations and inhibited by atrial natriuretic pepetide in both visceral mature adipocytes and in vitro-differentiated preadipocytes. Co-incubation with increasing Ang II concentrations and valsartan indicated that Ang II effects were AT1-mediated. Tallant et al 2005 The use of transfection of cultured myocytes with an antisense oligonucleotide to the mas receptor blocked in this model the ANG-(1-7)-mediated inhibition of serum-stimulated MAPK activation, whereas a sense oligonucle- otide was ineffective. These results suggested that ANG-(1-7) reduced the growth of cardiomyocytes through activation of the mas receptor. Tikellis et al 2003 This study showed by immunostaining that both ACE2 and ACE protein were localized predominantly to renal tubules. In the diabetic kidney, there was reduced ACE2 protein expression that was prevented by ACE inhibi- tor therapy. Vincent et al 2003 This study concludes that insulin specifi cally recruits fl ow to the microvasculture in skeletal muscle via a nitric oxide- dependent pathway and that this may be important to insulin’s overall action to regulate glucose disposal. Zisman et al 2003 This study showed that Ang-(1-7)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but it was mediated by at least two different angiotensinases. The fi rst, which demonstrated substrate preference for Ang I, was neutral endopeptidase-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.

In addition, the renal RAS is clearly activated in DM, the vascular wall with circulating substances and plasma with increased tissue Ang II (Giacchetti et al 2005) that cells (Cardillo and Panza 1998). It produces vasodilator and leads to the development of diabetic nephropathy, a major vasoconstrictor substances that are in balance under normal cause of end-stage renal disease. Blockade of the RAS could conditions. The health of the vascular net depends though thus reduce tissue Ang II levels, with benefi cial effects on on the normal operation of the endothelium. The endothelial cardiovascular and renal function. dysfunction has been considered an imbalance in which the The so-called metabolic syndrome, now regarded as a vasoconstrictor effects overcome the vasodilator ones in global epidemic, includes obesity, insulin resistance, dyslipid- the vascular tonus (Jansson 2007; Pechánová et al 2007). emia, and hypertension, often with hypertriglyceridemia and This imbalance leads to a decrease of NO activity, which reduced high-density lipoprotein, as well as hyperuricemia and implies in a damage of the vascular protection (Pechánová increased C-reactive protein (Meigs 2003). These features are et al 2007). The endothelium generally acts as a preventing often associated with endothelial cell dysfunction with impaired barrier to the exocytose of macrophages and of low-density control of vascular tone, increased adhesiveness of leukocytes, lipoproteins (LDL) to the subendothelium, and, thus protects and increased formation of growth factors and cytokines. These against the atherosclerosis process (Romeo et al 2007). processes have been implicated in the development of diabetes, The RAS can infl uence the vascular function by several hypertension, heart failure, atherosclerosis, and renal failure. In ways, and studies have shown AT1 and AT2 receptors in the this context, RAS components, mostly Ang II, have a potential endothelium cells (Jacques et al 2003), besides evidence of role in endothelial cell dysfunction, insulin resistance, infl am- Mas receptors, the Ang-(1-7) receptor (Sampaio et al 2007a, mation, and proliferative effects (Watanabe et al 2005). 2007b). Ang II generally exhibits a vasoconstrictor effect on the endothelium while Ang-(1-7) is preferentially a vasodila- Interactions between RAS, tor peptide (Sampaio et al 2007b). Thus, the balance of these endothelium, and insulin signaling angiotensins’ effects is probably involved in the maintenance pathways of endothelium integrity. It is well established that Ang II The endothelium is a dynamic autocrine and paracrine produces endothelial dysfunction through different pathways, organ that regulates vascular tonus and the interaction of such as increasing the oxidative stress (Agarwal 2003) and

794 Vascular Health and Risk Management 2008:4(4) RAS and diabetes

Table 2 Summary of recent clinical research on renin–angiotensin system

Author Results/Interpretations Bojestig et al 2000 PRA and Ang II concentrations were signifi cantly lower in diabetic patients than in the controls. The levels of atrial natriuretic peptide, on the other hand, were higher in patients than in controls. PRA correlated negatively to the mean value of HbA(1c) during the previous fi ve years. Brenner et al 2001 for the RENAAL Study Losartan reduced the incidence of a doubling of the serum creatinine concentration (risk reduction, 25%; P = 0.006) and end-stage renal disease (risk reduction, 28%; P = 0.002) but had no effect on the rate of death. Losartan conferred signifi cant renal benefi ts in patients with type 2 diabetes and nephropathy. Dahlof et al 2002 Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefi ts beyond reduction in blood pressure, and new-onset diabetes was less frequent with losartan. Gross et al 2007 The survey of specifi c functional polymorphisms of the RAS, namely the angiotensin-I-converting enzyme (ACE) D/I, the angiotensinogen (AGT) T174M and M235T, and A1166C of the angiotensin-II receptor 1 (AGTR1), revealed that the incidence recurrent in-stent restenosis in a high-risk cohort was not associated with any of the polymorphisms examined in this study. Gumprecht et al 2000 The results of this study suggest that ACE gene insertion/deletion and angiotensinogen M235T polymorphisms contribute to the increased risk for the development of chronic renal failure, HOPE 2000 Ramipril was benefi cial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefi t was shown to be greater than that attributable to the decrease in blood pressure. Lieb et al 2006 This study provides evidence that genetic variants in the ACE2 gene may be associated with left ventricular mass, septal wall thickness, and left ventricular hypertrophy in hemizygous men. Lewis et al 2001 The angiotensin-II-receptor blocker irbesartan was effective in protecting against the progres- sion of nephropathy due to type 2 diabetes. This protection was independent of the reduction in blood pressure it causes. Lindholm et al 2002 Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and left ventricular hypertrophy. Losartan seems to have benefi ts beyond blood pressure reduction. Matayoshi et al 2007 This study shows that the systemic RAS may modulate insulin sensitivity in essential hypertensive patients. Merrill et al 2002 This study demonstrates, for the fi rst time, increased plasma Ang-(1-7) in normal pregnant subjects compared with nonpregnant subjects and decreased Ang-(1-7) in preeclamptic subjects compared with normal pregnant subjects. Mukai et al 2002 The results of this study demonstrate that long-term inhibition of the renin-angiotensin system ameliorates endothelial dysfunction associated with aging through the inhibition of the synthesis of COX-2-derived vasoconstricting factors and superoxide anions. Nogueira et al 2007 This study suggests that reduced levels of the vasodilator Ang-(1-7) could be implicated in the endothelial dysfunction seen in gestational diabetic women during and after pregnancy. Parving et al 2001 This study showed that Irbesartan is renoprotective independently of its blood-pressure-lowering effect in patients with type 2 diabetes and microalbuminuria Simões e Silva et al 2006b This study showed different circulating RAS profi les between hypertensive and in normotensive chronic renal failure subjects. Marked changes in plasma Ang-(1-7) were associated with the presence of hypertension and progression of kidney dysfunction. Simões e Silva et al 2004 This study showed different RAS profi les in childhood hypertension and suggested a blood pres- sure-independent change of Ang-(1-7) in essential hypertension. Wijpkema et al 2006 In this study, the authors could establish a role for the AT1R 1166A/C polymorphism in restenosis after percutaneous coronary intervention. However, signifi cant gene – gene interaction was suggested for the ACE gene and the HO-1 promotor, meriting further investigation in restenosis. Winkelmann et al 1999 The signifi cant relations observed in this study between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating angiotensinogen in the pathogenesis of coronary artery disease.

(Continued)

Vascular Health and Risk Management 2008:4(4) 795 Ribeiro-Oliveira et al

Table 2 Continued Yang et al 2007 The results of this study indicate that common genetic variants in the ACE2 gene might impact on myocardial infarction in females, and may possibly interact with alcohol consumption to affect the risk of coronary heart disease and myocardial infarction in Chinese males. Yusuf et al 2001 This study demonstrated that ramipril is associated with lower rates of new diagnosis of diabetes in high-risk individuals. Zhong et al 2006 This study concluded that the ACE2 A/G polymorphism is associated with hypertension in patients with metabolic syndrome. Zisman et al 2003 This study showed that Ang-(1-7)-forming activity from both Ang I and Ang II was increased in failing human heart ventricles but it was mediated by at least two different angiotensinases. The fi rst, which demonstrated substrate preference for Ang I, was neutral endopeptidase-like. The second was ACE2, as demonstrated by Western blotting and inhibition of activity with C16.

exerting proliferative (Clark et al 2008) and prothrombotic Brosnihan et al 1996; Maia et al 2004). In addition, Ang activities (Spillert et al 1994; Watanabe et al 2005). Ang II (1-7) also inhibits the growth of VSMC (Freeman et al 1996), also stimulates the production of superoxide radicals, TGF-β, platelet aggregation and thrombosis (Kucharewicz et al 2002; endothelin, and plasminogen activator inhibitor (PAI-1), Fraga-Silva et al 2008), infl ammation, fi brosis (Pereira et al which ultimately interferes in NO action (Rodrigues et al 2007), and oxidative stress (Benter et al 2008), which in turn 2007). Thus, there is enough evidence that Ang II accumula- might lead to endothelial function restoration. tion damages the endothelium and leads to atherosclerosis Indeed, Ang-(1-7) can antagonize Ang II effects not only (Watanabe et al 2005; Cippolone et al 2006). However, by the stimulation of other vasodilators but also through AT1 other mediators are also responsible for endothelial function receptor inhibition. In this regard, Kostenis and colleagues regulation (Savoia and Schiffrin 2007). In this regard, the (2005) reported that Mas receptor seems to act as a physi- vasoconstriction actions produced by Ang II and endothelin ological antagonist of AT1 receptor and by so counteracts are probably opposed by the release of NO, prostaglandins, many Ang II actions (Figure 1). bradykinin as well as by Ang-(1-7). Furthermore, Ang-(1-7) Alterations in the synthesis and degradation of endothe- promotes the release of NO and prostaglandins (Brosnihan lial factors have recently been described as a contributor to et al 1996; Pörsti et al 1994) and potentiates bradykinin the beginning or maintenance of a series of complications, effects in different experimental models (Paula et al 1995; including changes in vascular reactivity, blood fl ow, and tissue perfusion, which are all present in diabetes, renal diseases, heart failure, and hypertension (Kang et al 2002; Simões e INSULIN Silva et al 2006c; Nakagawa et al 2007). Recently, studies have shown the presence of reduced levels of Ang-(1-7) in Insulin receptor pregnancy complicated by pre-eclampsia (Merril et al 2002) and gestational diabetes (Nogueira et al 2007), corroborating to the hypothesis that changes in circulating levels of Ang-(1- Ang II MAP-K PI3-K 7) can be a marker of a new onset endothelial dysfunction. Clinical and experimental evidence show that ACE Celullar growth Glucose transport inhibitors and AT1 receptor blockers clearly improve endo- Celullar movement eNOS stimulation thelial dysfunction. Many mechanisms might take part in this l PAI 1 effect and one of them is the increase of bradykinin levels with

l MCP 1 ACE inhibitors (Weir 2007). Considering that the treatment with RAS blockers (ACE inhibitors and AT receptor block- l ICAM 1 1 ers) also increases Ang-(1-7) levels (Campbell 2003; Simões Figure 2 Interactions between angiotensin II and insulin receptor in vascular smooth e Silva et al 2006b), our group and other investigators have muscle cells. Abbreviations: Ang II, angiotensin II; MAPK, mitogen-activated protein kinase; PAI speculated that the benefi cial action of RAS blockade could 1, plasminogen activator inhibitor-1; MCP 1, monocyte chemoattractant protein be, at least in part, due to Ang-(1-7) effects (Simões e Silva 1; ICAM 1, intracellular cell adhesion molecule-1; PI3K, inositol 3-phosphatidil kinase; eNOS, endothelial nitric oxide synthase. et al 2006a; Santos and Ferreira 2007; Chappell 2007).

796 Vascular Health and Risk Management 2008:4(4) RAS and diabetes

In regard to diabetes, ACE inhibitors have also been recruitment and of the total blood fl ow to the skeletal muscle associated to a decrease in the incidence of type 2 diabetes (Velloso et al 2006). The blunted endothelium NO-release in hypertensive patients (Yusuf et al 2001; Vijayaraghavan has also been implicated in the reduction of capillary recruit- and Deedwania 2005; Schmieder et al 2007), besides their ment and of total blood fl ow, leading to a state of low glucose wide spread utilization to prevent renal and cardiovascular availability that characterizes insulin resistance (Hsueh and diabetes complications (Weir 2007). Recent studies have Quiñones 2003; Vincent et al 2003). shown an interaction between RAS and the insulin signaling Besides its NO-dependent effects in the vascular pathways through AT1 receptors (Velloso et al 2006), and endothelium, insulin also interferes with hemodynamic the utilization of AT1 receptor blockers have shown simi- homeostasis in insulin resistant states (Yki-Jarvinen 2003). lar protective effects on renal and cardiovascular diabetes In these conditions, insulin can act through MAP-K pathway, complications (Brenner et al 2001; Lindholm et al 2002). promoting cellular growth and other pro-inflammatory While Ang II may contribute to endothelial dysfunction and and pro-thrombotic actions (Velloso et al 2006). In obese chronic diabetes complications, especially in the presence individuals, it has been speculated a possible shift from PI3-K of insulin resistance (Hsueh and Quiñones 2003), treatment pathway, the molecular via for insulin signal transduction with ACE inhibitors or AT1 receptor blockers has shown to into action, to the MAP-K pathway, offering a molecular be protective in diabetes (Brenner et al 2001; Lindholm et al explanation by which hyperinsulinemia of these individuals 2002). However, these studies have not addressed the pos- might play a pro-atherogenic role (Hsueh and Quiñones 2003). sible role of Ang-(1-7) in this unclear mechanism by which There is also a possible interaction between insulin and local

ACE inhibitors or AT1 receptor blockers prevent diabetes RAS at this level, since Ang II through AT1 receptors may complications and novel diabetes onset. stimulate the MAP-K pathway and, by doing so, promotes cellular proliferation, infl ammation and thrombosis (Velloso Interactions between endothelial et al 2006), while the activation of AT2 receptors could inhibit factors and insulin signaling this same via, meanwhile activating PI3-K (Bedecs et al 1997) Several studies in humans and animals have shown that insu- (Figure 3). Although a possible antiproliferative action of lin stimulated NO from the vascular endothelium represents Ang-(1-7) in this scenario is only speculative, experimental an important physiologic role in the increase of the capillary evidence with cardiomyocytes (Tallant et al 2005), pulmonary

HYPERGLICEMIA HYPERINSULINEMIA

ANGIOTENSINOGEN Ang (1-9)

RENIN ACE 2 Endopeptidases INSULIN Ang I Ang (1-7)

ECA

Ang ECA 2 PI3 K MAPK

Ang II L-Arginin

eNOS BRADYKININ

Ang II

ALDOSTERONE NITRIC OXIDE

PROSTAGLANDINS Receptor Receptor Receptor

AT2 ENDOTHELIUM

ICAM-1 VCMS PAI-1 TXA2 ET1 VASODILATION ROS VASOCONSTRICTION

Figure 3 Interactions between renin–angiotensin system, kinin–kallikrein system, and insulin signaling transduction pathways. Abbreviations: MAPK, mitogen-activated protein kinase; PI3K, inositol 3 phosphatidil kinase; Ang, Angiotensin; ACE, angiotensin-converting enzyme; ACE2, angiotensin-convert- ing enzyme 2; AT1, AT 2, angiotensinergic receptors types 1 and 2; Mas, Mas receptor of angiotensin-(1-7); NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; ET1, endothelin 1; TXA2, thromboxane A2; PAI 1, plasminogen activator inhibitor; VCMS, vascular smooth muscle cell; ICAM1, intracellular adhesion molecule 1.

Vascular Health and Risk Management 2008:4(4) 797 Ribeiro-Oliveira et al tumor cells (Gallagher and Tallant 2004), and liver tissue Bojestig et al 2000). For example, in diabetes nephropathy, (Pereira et al 2007; Herath et al 2007; Warner et al 2007) studies have shown a suppression of plasma renin activ- corroborates this possibility. ity (Bjork 1990), while tissue renin are generally elevated In addition, many studies have reported a connection (Anderson et al 1993). Therefore, although the evaluation between insulin resistance and RAS (Matayoshi et al 2007). of the circulating RAS components may be of importance, It was shown that Ang II infusion induced insulin resistance it may not give full information of intra renal RAS compo- (Richey et al 1999) and the blockade of the RAS improved nents. insulin sensibility (Furuhashi et al 2004). In this regard, Adipose tissue secretes a variety of hormones (known Santos and colleagues (2008) recently reported that, despite collectively as adipokines) that can modulate endothelial normal body weight, Mas-knockout mice in FVB/N back- function. For example, TNF-α is a proinfl ammatory cytokine ground presented dyslipidemia, increased levels of insulin secreted by adipose cells that may cause insulin resistance and and leptin, and an approximately 50% increase in abdominal endothelial dysfunction (Rydén and Arner 2007). In addition, fat mass. Mas deletion also led to glucose intolerance and components of RAS, including AGT, renin, ACE, Ang II, reduced insulin sensitivity as well as a decrease in insulin- and the AT1 and AT2 receptors are present in adipose tissue stimulated glucose uptake by adipocytes and decreased (Sarzani et al 2008). Ang II, through AT1 receptor, is able to GLUT4 in adipose tissue. These results indicated that Mas modulate insulin actions, and this may be due to inhibition of defi ciency in FVB/N mice induces a metabolic syndrome- cross-talk between Ang II signaling and insulin signaling in like state. Further studies are obviously necessary to address metabolic and vascular tissues (Caglayan et al 2005). In this the pathophysiological role of ACE2-Ang-(1-7)-Mas axis in regard, the addition of Ang II to endothelial cells activates human diabetes. MAP-K pathways, leading to increased serine phosphory- lation of IRS-1, impaired PI3-K activity, and endothelial

RAS, diabetes, and the endothelium dysfunction, which is abolished by AT1 receptor blockers The cardiovascular morbidity and mortality related to dia- (Nakashima et al 2006). In addition to effects on insulin betes, especially type 2 diabetes, are very high. Recently, signaling, the activation of AT1 receptors stimulates the cardiovascular risk has been reaching enormous proportions production of ROS via NADPH oxidase, increases expres- due to the obesity epidemic, metabolic syndrome, and type 2 sion of ICAM-1, and ET-1 release from the endothelium diabetes. Large clinical trials have been conducted to address (Caglayan et al 2005). Therefore, there are multiple direct the increase in renal and cardiovascular complications in the and indirect mechanisms by which RAS contribute to insulin diabetic patient. The results of United Kingdom Prospective resistance and endothelial dysfunction through the modula- Diabetes Study (UKPDS), Reduction of Endpoints in Non- tion of insulin signaling and other metabolic and vascular Insulin-Dependent Diabetes Mellitus with the Angiotensin pathways (Caglayan et al 2005), supporting the therapeutic II Antagonist Losartan (RENAAL), Irbesartan Diabetic institution of RAS inhibition. Nephropathy Trial (IDNT) Patients with Type 2 Diabetes and RAS blockade may be achieved through the inhibition of Microalbuminuria Study (IRMA2), and Heart Outcomes Pre- Ang II formation (with ACE or renin inhibitors), and through vention Evaluation (HOPE and MICRO-HOPE) have shown direct inhibition of AT1 receptors. In clinical scenario, ACE that a well defi ned treatment of diabetic patients translated inhibitors and AT1 receptor blockers have been considered into renal and cardiovascular protection. Through these stud- the most important ways of RAS blockade. The mechanism ies, it is now well established that prevention or reduction of action of ACE inhibitors results in accumulation of BK, in proteinuria, blood pressure control, glycemic control, and whereas it does not occur with the AT1 receptor blockers. particularly, the blockade of RAS are essential to prevent or Other differences include the blockade of Ang II formation delay the vascular diabetes complications. As already men- through ACE-independent pathways by AT1 receptor block- tioned, RAS blockade has been shown not only a protective ers (Li et al 2004), and a more prominent reduction of plasma effect upon renal and cardiovascular complications of type 2 blood fl ow by AT1 receptor blockers and renin inhibitors (Li diabetes (Weir 2007), but also reduce novel type 2 diabetes et al 2004). However, these agents have exhibited similar onset in hypertensive patients as shown by HOPE (Lindholm benefi cial results in renal and cardiovascular diabetes com- et al 2002) and LIFE studies (Dahlof et al 2002). plications (Yusuf et al 2001; Lindholm et al 2002). Studies of RAS in diabetes have shown confl ictive results In the HOPE study, diabetes incidence was lower in the regarding the activation of this system (Price et al 1999; group treated with ramipril when compared with placebo

798 Vascular Health and Risk Management 2008:4(4) RAS and diabetes

(Yusuf et al 2001). In the LIFE (Losartan Intervention For resistance and the elevated free fatty acids may also stimulate Endpoint Reduction in Hypertension) study, the use of renal Ang II generation, thus contributing to the pathogenesis losartan was associated with a reduction in the occurrence of diabetes nephropathy (Carey and Siragy 2003b; Kalantrina of new diabetes onset as compared with atenolol (Lindholm and Okusa 2006). Furthermore, in the diabetic kidney, there et al 2002). Although the precise mechanisms involved on the was reduced ACE2 protein expression that was prevented reduction of new type 2 diabetes diagnosis by RAS inhibi- by ACE inhibitor therapy (Tikellis et al 2003). tion are not well established, the increase in insulin mediated Many studies have also proven the role of ACE2 as a glucose uptake (Jamerson et al 1996), the improvement of protective enzyme for cardiovascular diseases (see Table endothelial function (Mukai et al 2002), a decrease in infl am- 2). As the ACE2 gene is on the X chromosome, the studies matory response (Mervaala et al 1999), an increase in BK correlating the ACE2 gene polymorphisms with cardiovas- and Ang-(1-7) levels (Maia et al 2004), and an effect in local cular and metabolic diseases have to take the gender into system in the pancreatic islets (Lau et al 2004) have been consideration meanwhile performing data analyses (Lieb et al suggested as some of the putative factors (Cooper et al 2006). 2006; Zhong et al 2006; Yang et al 2007). Although there is a To date, many studies have placed RAS inhibition as of great lack of studies in this fi eld, particularly in diabetes, a Chinese importance to prevent cardiovascular diabetes complications study has shown that patients with the metabolic syndrome (HOPE, LIFE, and RENAAL Studies). exhibit an association of ACE2 gene A/G polymorphism and Concerning its preventive actions in type 2 diabetes, RAS elevated blood pressure (Zhong et al 2006). Further studies inhibition has also been shown to improve insulin sensitiv- should investigate the importance of these polymorphisms in ity, allowing a better insulin action or a reduction in insulin diabetes, and also verify if the known polymorphisms in the dosages in some patients (De Mattia et al 1996). Several RAS genes that have been studied in restenosis after percu- studies, utilizing clamps for insulin sensibility evaluation, taneous coronary intervention (Gross et al 2007; Wijpkema have confi rmed these data in patients receiving ACE inhibi- et al 2006) would also play a prominent role in diabetes and tors or AT1 blockers (Yki-Jarvinen 1995). coronary disease. RAS inhibition is of importance in the prognosis of renal Therefore, the identifi cation of ACE2 in the kidney and diabetes complications of both type 1 and type 2 diabetes. cardiovascular system, its modulation in diabetes, and the Renal Ang II increases the capillary glomerular pressure, recent description that this enzyme plays a biological role which ultimately translates into hyperfi ltration and protein- in the generation and degradation of various angiotensin uria (Navar et al 2000; Brewster and Perazella 2004). Delete- peptides provide a rationale to further explore the role of rious Ang II effects have been demonstrated in experimental ACE2-Ang-(1-7)-Mas axis in diabetic complications. studies in which its infusion resulted in increase of intraglo- merular pressure and protein excretion (Doria et al 1997). Concluding remarks The resulting proteinuria associates to arterial hypertension In conclusion, this review shows the physiology of the RAS, and to the elevated risk of end stage renal disease, besides including the importance of novel mediators, receptors, and predicting cardiovascular complications of type 2 diabetes enzymatic pathways. It also shows how the current view of this (Mogensen 1984; Deckert 1994). The benefi cial effects system might impact diabetes and its complications, highlight- of ACE inhibitors or AT receptor blockers upon diabetes 1 ing the importance of RAS inhibition in this disease treatment. nephropathy have been understood, at least in part, as a Furthermore, we also provide recent evidence for putative role result of the attenuation of Ang II effects on blood pressure of ACE2-Ang-(1-7)-Mas axis in diabetes pathogenesis. and glomerular hemodynamics (Carey and Siragy 2003b; Kalantrina and Okusa 2006). Besides these hemodynamic Disclosure actions, Ang II also stimulates TGFβ 1 and protein kinase The authors report no confl ict of interest. C through AT1 receptors and thus increases extracellular matrix and vascular permeability (Kagami et al 1994; Wolf and Ziyadeh 1997; Carey and Siragy 2003b). These effects References Abdalla S, Lother H, Quitterer U. 2000. AT1-receptor heterodimers show are quite similar to the results obtained with chronic hyper- enhanced G-protein activation and altered receptor sequestration. glycemia on the kidney, suggesting that the harmful renal Nature, 407:94–8. Agarwal R. 2003. Proinfl ammatory effects of oxidative stress in chronic hyperglycemic effects may be partially mediated by Ang II kidney disease: role of additional angiotensin II blockade. Am J Physiol (Singh et al 1999). Of interest, hyperglycemia, the insulin Renal Physiol, 284:F863–9.

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